Ligand-therapeutic agent conjugates, silicon-based linkers, and methods for making and using them

a technology of ligand-therapeutic agent and conjugate, which is applied in the field of conjugate compounds and silicon linker compounds, can solve the problems of being too labile to achieve the long plasma half-lives desired for the intact conjugate, and achieve the effect of long plasma half-lives

Inactive Publication Date: 2016-05-31
ALBANY MOLECULAR RESEARCH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0099]In accordance with the present invention, the right balance between releasing group stability and lability is achieved for linkers useful in ligand-therapeutic agent conjugates. To use the common releasing technologies, the therapeutic agent may require a specific functional group or must be appended with the desired group without affecting the drug's potency. For example, PAB technology normally uses amine-bearing drugs. An alternative method to release a drug moiety is provided herein. Attachment of the therapeutic agent via a common functional group, such as a hydroxyl group, is ideal since such groups are often found on natural product or natural product-based cytotoxics. Although commonly used as intermediates in organic synthesis, the use of silyl ether compounds found in the present invention as releasing moieties in the field of immunotoxins (i.e. antibody drug conjugates) or more broadly to targeted drug delivery, such as folate conjugates, can overcome the above limitations in the field of drug delivery. In the ligand-therapeutic agent conjugates herein, the therapeutic agent is preferentially cleaved at a particular cell or tissue type targeted by the ligand.

Problems solved by technology

Certain other functional moieties have been used such as esters, but esters often can be too labile to achieve the long plasma half-lives desired for the intact conjugate.

Method used

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  • Ligand-therapeutic agent conjugates, silicon-based linkers, and methods for making and using them
  • Ligand-therapeutic agent conjugates, silicon-based linkers, and methods for making and using them
  • Ligand-therapeutic agent conjugates, silicon-based linkers, and methods for making and using them

Examples

Experimental program
Comparison scheme
Effect test

example 1

General Procedures

[0393]Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on Bruker spectrometers at 300 or 500 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Mass spectra were collected using a Waters SQ Detector single quadripole mass spectrometer (ESI). High performance liquid chromatograph (HPLC) analyses were obtained using a Luna C18(2) column (250×4.6 mm, Phenomenex, Torrance, Calif.) with UV detection at 254 nm using the standard solvent gradient programs Method A or Method B:

[0394]

Method A:TimeFlow(min)(mL / min)% A% B0.01.090.010.020.01.00.0100.025.01.00.0100.027.01.090.010.032.01.090.010.0A = Water with 0.1% Trifluoroacetic AcidB = Acetonitrile with 0.1% Trifluoroacetic Acid

[0395]

Method B:TimeFlow(min)(mL / min)% A% B0.0880.020.010.01.00.0100.012.01.00.0100.014.01.080.020.016.0...

example 2

Preparation of benzyl 5-(chlorodimethylsilyl)pentanoate

[0396]

[0397]To a mixture of chlorodimethylsilane (0.730 g; 6.57 mmol) and benzyl pent-4-enoate (1.25 g; 6.57 mmol) under argon was added one drop of Karstedt's catalyst solution (in xylenes; ˜2% Pt). The reaction vessel was sealed and the mixture was heated to 60° C. for 13.5 hours. The crude liquid was used without purification.

example 3

Preparation of benzyl 5-(chlorodiphenylsilyl)pentanoate

[0398]

[0399]To a mixture of chlorodiphenylsilane (0.49 g; 2.58 mmol) and benzyl pent-4-enoate (0.50 g; 2.58 mmol) under argon was added two drops of Karstedt's catalyst solution (in xylenes; ˜2% Pt). The reaction vessel was sealed and the mixture was heated to 60° C. for 15 hours. The crude liquid was used without purification.

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Abstract

The present invention relates to ligand-therapeutic agent conjugate compounds, silicon linkers for the conjugate compounds, compositions, methods for making them, and methods for the treatment of cancer using the conjugate compounds. The silicon-based linkers described herein can be used to deliver desired therapeutic agents to particular cells or tissue types targeted by the ligand.

Description

[0001]This application claims the priority benefit of U.S. Provisional Patent Application Ser. No. 61 / 784,906, filed Mar. 14, 2013, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to conjugate compounds, silicon linker compounds, compositions, methods for making them, and methods for the treatment of diseases using the conjugate compounds. In particular, the present invention relates to such compounds, compositions, and methods, where the compounds include novel silicon linkers.BACKGROUND OF THE INVENTION[0003]Drug delivery technology has been used extensively for the purpose of delivering agents to desired targets for many years. A variety of methods and routes of administration have been developed to deliver pharmaceuticals, such as small molecular drugs and other biologically active compounds (e.g., peptides, hormones, proteins, and enzymes). Examples of various drug delivery methods are disclosed, for example, i...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K47/48C07D519/04A61K38/00
CPCA61K47/48107A61K38/00A61K47/48384A61K47/48715C07D519/04A61K47/6889A61K47/551A61K47/6803A61K31/337A61K31/475A61P35/00Y02A50/30
Inventor GUZZO, PETER R.MANNING, DAVID D.
Owner ALBANY MOLECULAR RESEARCH INC
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